Formulación y evaluación in vitro de un sistema conjugado "quitosano - enrofloxacino" como alternativa en el tratamiento de endometritis subclínica en vacas

La endometritis, inflamación del endometrio usualmente debido a la persistencia de una infección o al retraso en la involución uterina, es uno de los principales factores que afectan la eficiencia reproductiva del vacuno lechero retrasando el retorno de la vaca en sus actividades reproductivas. En ausencia de signos clínicos de endometritis, las modificaciones del endometrio uterino pueden ser definidas como endometritis subclínicas (ES) que se caracterizan por la presencia y aumento de Polimorfo Nucleares Neutrófilos (PMN) en el lumen uterino sin descargas purulentas.Trabajo de investigació

Facilitated Monocyte-Macrophage Uptake and Tissue Distribution of Superparmagnetic Iron-Oxide Nanoparticles

BACKGROUND: We posit that the same mononuclear phagocytes (MP) that serve as target cells and vehicles for a host of microbial infections can be used to improve diagnostics and drug delivery. We also theorize that physical and biological processes such as particle shape, size, coating and opsonization that affect MP clearance of debris and microbes can be harnessed to facilitate uptake of nanoparticles (NP) and tissue delivery. METHODS: Monocytes and monocyte-derived macrophages (MDM) were used as vehicles of superparamagnetic iron oxide (SPIO) NP and immunoglobulin (IgG) or albumin coated SPIO for studies of uptake and distribution. IgG coated SPIO was synthesized by covalent linkage and uptake into monocytes and MDM investigated related to size, time, temperature, concentration, and coatings. SPIO and IgG SPIO were infused intravenously into naïve mice. T(2) measures using magnetic resonance imaging (MRI) were used to monitor tissue distribution in animals. RESULTS: Oxidation of dextran on the SPIO surface generated reactive aldehyde groups and permitted covalent linkage to amino groups of murine and human IgG and F(ab')(2) fragments and for Alexa Fluor(R) 488 hydroxylamine to form a Schiff base. This labile intermediate was immediately reduced with sodium cyanoborohydride in order to stabilize the NP conjugate. Optical density measurements of the oxidized IgG, F(ab')(2), and/or Alexa Fluor(R) 488 SPIO demonstrated approximately 50% coupling yield. IgG-SPIO was found stable at 4 degrees C for a period of 1 month during which size and polydispersity index varied little from 175 nm and 200 nm, respectively. In vitro, NP accumulated readily within monocyte and MDM cytoplasm after IgG-SPIO exposure; whereas, the uptake of native SPIO in monocytes and MDM was 10-fold less. No changes in cell viability were noted for the SPIO-containing monocytes and MDM. Cell morphology was not changed as observed by transmission electron microscopy. Compared to unconjugated SPIO, intravenous injection of IgG-SPIO afforded enhanced and sustained lymphoid tissue distribution over 24 hours as demonstrated by MRI. CONCLUSIONS: Facilitated uptake of coated SPIO in monocytes and MDM was achieved. Uptake was linked to particle size and was time and concentration dependent. The ability of SPIO to be rapidly taken up and distributed into lymphoid tissues also demonstrates feasibility of macrophage-targeted nanoformulations for diagnostic and drug therapy

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Immunociblage du cerveau par des nanocapsules lipidiques

Cette thèse porte sur l'élaboration d'un vecteur particulaire lipidique reconnaissant activement les tissus cérébraux après son administration par voie intraveineuse. Ce système devrait favoriser l accumulation au sein du cerveau, de molécules thérapeutiques dans le cadre du traitement des maladies cérébrales comme les gliomes malins. La première partie de notre travail consistait à greffer sur la surface de nanocapsules lipidiques (LNC) des anticorps monoclonaux d origine murine (OX26) ou des fragments Fab dirigés contre le récepteur à la transferrine de rat, surexprimé sur l endothélium cérébral. Des immunonanocapsules portant entre 16 et 183 anticorps entiers et entre 42 et 173 fragments Fab ont été obtenues. Leur capacité à s associer aux cellules endothéliales cérébrales de rat a ensuite été vérifiée. De plus, 24 h après leur administration chez le rat, la concentration dans le cerveau des OX26- immunonanocapsules et des Fab -immunonanocapsules était respectivement 2 et 1,5 fois plus élevée que celle des LNC dépourvues de ligands.This thesis concerns the development of a lipidic nanovector recognizing actively the cerebral tissues after its intravenous administration. This system should promote the accumulation into the brain, of therapeutic molecules for the treatment of cerebral diseases such as the malignant gliomas. The first part of our work consisted to attach on the surface of lipid nanocapsules, murine monoclonal antibodies (OX26) or Fab fragments directed against the rat transferrin receptor, overexpressed on the cerebral endothelium. Immunonanocapsules bearing between 16 and 183 whole antibodies and between 42 and 173 Fab fragments were achieved. Their capacity to associate to rat cerebral endothelial cells has then been checked. Moreover, 24 after their intravenous administration in rats, the concentration of OX26-immunonanocapsules and Fab -immunonanocapsules was 2 and 1.5-fold higher than non-targeted nanocapsules.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Immunociblage du cerveau par des nanocapsules lipidiques

Cette thèse porte sur l'élaboration d'un vecteur particulaire lipidique reconnaissant activement les tissus cérébraux après son administration par voie intraveineuse. Ce système devrait favoriser l accumulation au sein du cerveau, de molécules thérapeutiques dans le cadre du traitement des maladies cérébrales comme les gliomes malins. La première partie de notre travail consistait à greffer sur la surface de nanocapsules lipidiques (LNC) des anticorps monoclonaux d origine murine (OX26) ou des fragments Fab dirigés contre le récepteur à la transferrine de rat, surexprimé sur l endothélium cérébral. Des immunonanocapsules portant entre 16 et 183 anticorps entiers et entre 42 et 173 fragments Fab ont été obtenues. Leur capacité à s associer aux cellules endothéliales cérébrales de rat a ensuite été vérifiée. De plus, 24 h après leur administration chez le rat, la concentration dans le cerveau des OX26- immunonanocapsules et des Fab -immunonanocapsules était respectivement 2 et 1,5 fois plus élevée que celle des LNC dépourvues de ligands.This thesis concerns the development of a lipidic nanovector recognizing actively the cerebral tissues after its intravenous administration. This system should promote the accumulation into the brain, of therapeutic molecules for the treatment of cerebral diseases such as the malignant gliomas. The first part of our work consisted to attach on the surface of lipid nanocapsules, murine monoclonal antibodies (OX26) or Fab fragments directed against the rat transferrin receptor, overexpressed on the cerebral endothelium. Immunonanocapsules bearing between 16 and 183 whole antibodies and between 42 and 173 Fab fragments were achieved. Their capacity to associate to rat cerebral endothelial cells has then been checked. Moreover, 24 after their intravenous administration in rats, the concentration of OX26-immunonanocapsules and Fab -immunonanocapsules was 2 and 1.5-fold higher than non-targeted nanocapsules.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Preparation and characterization of PLGA nanoparticles

International audienc

Prise en charge du sportif à l'officine dans le cadre d'un traitement homéopathique

BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

Interspecies differences in the cytochrome P450 activity of hepatocytes exposed to PLGA and silica nanoparticles: an in vitro and in vivo investigation

International audienceThis study emphasizes the interest to set up relevant in vitro models using human hepatic cells to evaluate the hepatotoxicity of nanomedicines

Nanoparticle-based delivery enhances anti-inflammatory effect of low molecular weight heparin in experimental ulcerative colitis

<p>Epithelial administration of low molecular weight heparin (LMWH) has proven its therapeutic efficiency in ulcerative colitis (UC) but still lacks of a sufficiently selective drug delivery system. Polymeric nanoparticles were used here not only to protect LMWH from intestinal degradation but also to provide targeted delivery to inflamed tissue in experimental colitis mice. LMWH was associated with polymethacrylate nanoparticles (NP) type A (PEMT-A) or type B (PEMT-B) of a size: 150 nm resulting in a maximum drug loading: 0.1 mg/mg. In a lipopolysaccharide-stimulated macrophages both, free LMWH and LMWH-NP have significantly reduced the cytokines secretion independently from cellular uptake. The <i>in-vivo</i> therapeutic efficiency was dose dependent as at low doses (100 IU/kg) only minor differences between free LMWH and LMWH-NP were found and the superiority of LMWH-NP became prominent with dose increase (500 IU/kg). Administration of LMWH-NP at 500 IU/kg has markedly improved the clinical activity as compared to LMWH while similarly pathophysiological indicators revealed increased therapeutic outcome in presence of NP compared to LMWH alone: Myeloperoxidase (Colitis control: 10 480 ± 5335, LMWH-PEMT-A NP: 1507 ± 2165, LMWH-PEMT-B NP: 382 ± 143, LMWH: 8549 ± 5021 units/g) and tumor necrosis factor: (Colitis control: 1636 ± 544, LMWH-PEMT-A NP: 511 ± 506, LMWH-PEMT-B NP: 435 ± 473, LMWH: 1110 ± 309 pg/g). Associating LMWH with NP is improving the anti-inflammatory efficiency of LMWH <i>in-vivo</i> by its protection against degradation in luminal environment and selective drug delivery. Such a combination holds promise for a highly specific therapy by its double selectivity towards the inflamed intestinal tissue. LMWH-PEMT NP have significantly improved the clinical activity <i>in-vivo</i> in comparison to free LMWH.</p